Developmental changes of the contingent negative variation in migraine and healthy children

It has been hypothesized that abnormalities of information processing in migraine may be attributed to impairment of cerebral maturation. However, the most evidences for this hypothesis have come from cross-sectional studies during childhood. We performed a longitudinal study and recorded contingent negative variation (CNV), an event-related slow cortical potential, in migraine children (n = 27) and age-matched healthy individuals (n = 23) in 1998 and 8 years later (2006). Amplitudes of all CNV components were reduced and habituation of the initial CNV (iCNV) increased in the observed time. However, the reduction of the iCNV amplitude was more pronounced in migraine patients who were in remission in 2006 and in healthy subjects and less pronounced in migraineurs with persisting headaches. Patients with the worsened migraine demonstrated the most pronounced loss of iCNV habituation in 1998 and significantly increased iCNV amplitudes in 2006. This longitudinal study supports the hypothesis of impaired cerebral maturation in migraine and shows that migraine manifestation is a key factor interfering with the natural maturation process of central information processing.     

Contingent negative variation and efficacy of beta-blocking agents in migraine

Thirty-three patients with common migraine underwent contingent negative variation (CNV) recordings before receiving prophylactic beta-blocker treatment with either metoprolol (27 patients) or propranolol (6 patients) at mean daily dosages of 110 mg and 122 mg, respectively. After 3 months the therapeutic efficacy of the beta-blocker was assessed in each patient by means of a global severity score and compared with the initial CNV recordings. The mean clinical improvement was 62%. A significant positive correlation was found between CNV amplitude before prophylaxis and the clinical response to beta-blockers: patients with higher CNV tended to respond better to therapy. Eight of 10 patients with a CNV amplitude higher than -25 microV had a more than 50% reduction of the severity score--that is, a good or excellent response to the beta-blocking agent--whereas only 2 of 9 patients with an amplitude lower than -20 microV had a good response.     

Migräne als Reizverarbeitungsstörung?

Several studies of contingent negative variation (CNV) examined whether this method provides a suitable basis for research on pathogenetic processes in chronic headaches-especially migraine. In the present study, the CNV amplitudes and CNV course of 23 migraine patients were compared with those of 22 healthy subjects. CNV was calculated for (a) "total interval", (b) "early CNV component", and (c) "late CNV component". In 32 trials with an interstimulus interval of 3 s results showed a significant higher CNV in the migraine group. While the amplitude of healthy subjects diminished quickly, the amplitudes of migraine patients remained stable during the session. The results allow the assumption that the higher level of CNV amplitude in migraine patients is not only due to higher cortical noradrenergic or serotoninergic activation. This study shows that migraine patients cannot decrease their CNV amplutides. This is probably due to defective processing of sensory imput.     

Effects of pregnancy on slow cortical potentials in migraine patients and healthy controls

Increased negative amplitudes and lack of habituation of contingent negative variation (CNV) in migraine are well established and are supposed to reflect an altered cortical excitability level. Migraine attacks occur less during pregnancy but often relapse after delivery. We investigated the effect of pregnancy on slow cortical potentials and reaction time in migraine patients and healthy controls. Four groups were examined: 14 pregnant migraine patients, 12 non-pregnant migraine patients, 15 pregnant healthy women and 16 non-pregnant healthy women aged 19-38 years. Two recordings were performed in the pregnant subjects: in the 36th week of gestation and 4 weeks after delivery. The non-pregnant subjects were recorded at the same time interval of 8 weeks. Pregnant migraine patients showed significantly fewer migraine days during the third trimester of pregnancy and returned to nearly the former level 4 weeks post delivery. Non-pregnant migraine patients demonstrated a significant reduction of migraine days at the second measurement. There was no effect of pregnancy on CNV amplitudes, but there was an effect of pregnancy on the habituation coefficient and reaction time of migraine patients. Faster habituation from a higher preactivation level was found. As an explanation for the changed habituation level we favour the model of correlation between preactivation level and habituation level, the so-called law of initial value. We found a correlation between preactivation level and habituation. Our study confirms a specific effect of pregnancy on slow cortical potentials in migraine patients.     

Interictal and postictal contingent negative variation in migraine without aura

Cortical hyperexcitability is thought to explain the more enhanced contingent negative variation (CNV) amplitudes and impaired CNV habituation that have been found during the interictal period in migraine without aura. These CNV characteristics have been shown to normalize to the level of healthy controls during an attack. This study aimed to replicate the interictal findings, and additionally examine whether migraineurs show reduced CNV amplitudes during the postattack period. Of 12 patients with migraine without aura and their sex- and age-matched healthy controls, CNV characteristics were recorded once in an interictal period, once during the postattack period within 30 hours after an attack that was treated with sumatriptan, and once after an attack that was treated with habitual nonvasoactive medication (counterbalanced). The present results did not confirm the enhanced CNV early and late wave amplitudes or impaired habituation, and cortical hyperexcitability that have previously been reported in the interictal period in patients with migraine without aura. During the postattack period, a decrease in CNV early and late amplitudes was found but only after sumatriptan use. This reduction in CNV amplitudes was most prominent over the frontal cortex and could reflect cortical hypoexcitability, possibly related to a suppression of central catecholaminergic activity by sumatriptan.     

Longitudinal assessment of response preparation and evaluation in migraine gives evidence for deviant maturation

Evidence for deviant maturation of sensory processing in migraine has come recently from cross-sectional studies during childhood. Age-dependent development of response preparation and evaluation is characterized using a longitudinal design in school-aged migraine patients and controls in order to challenge the hypothesis of migraine as a maturation disorder. Forty-six children with migraine and 57 healthy controls aged 6–18 years were investigated and followed up 4 years later using a simple acoustic contingent negative variation (CNV) paradigm. Maturation in controls was characterized by increasing negativity of late and total CNV and stability of initial CNV (iCNV) and the motor postimperative negative variation (mPINV). Migraine patients showed a lack of development for late and total CNV and decreasing iCNV and mPINV negativity. This first longitudinal study confirms cross-sectional results of deviant CNV maturation in migraine. Altered maturation was not correlated with clinical improvement and may represent a vulnerability marker for migraine.     

Comparison of Contingent Negative Variation Between Migraine Interval and Migraine Attack Before and After Treatment With Sumatriptan

SYNOPSIS
We compared in a placebo controlled, double blind, cross-over within-subject design, the amplitude and area integral of contingent negative variation (CNV) using a 2 second interstimulus interval in migraine patients between attack and interval before and after treatment. The study was conducted on 14 female subjects suffering from migraine without aura. The measurements were performed in a balanced sequence at four different times on each patient, twice during the migraine interval and once in each of two migraine attacks. The CNV in the patients was measured first (baseline), then medication was administered on a double-blind basis with an auto-injector, using either 6 mg sumatriptan or a placebo solution. Thirty minutes after administration the CNV parameters were measured again and the changes between pre-and post-treatment were taken as dependent variables. CNV amplitude baseline readings did not differ significantly between the four conditions, Neither administration of placebo nor sumatriptan led to a significant change in CNV parameters independent of whether significant clinical improvement of migraine headache occurred or not. According to our findings CNV-mechanisms between attack and interval are not subject to short-term changes, even though a small, not significant tendency towards · decrease in CNV amplitude during migraine attacks appears to exist. Therefore, it can be assumed that changes in the systems which are depicted by CNV readings are not involved in initiating and terminating acute migraine attacks.     

Stereotyped topography of different elevated contingent negative variation components in children with migraine without aura points towards a subcortical dysfunction

Increased negativity during contingent negative variation (CNV) is thought to reflect abnormal neural activation in adult migraineurs' attention related processing. Findings in childhood and adolescence have yielded less clear results. This study characterizes the age-dependent development of CNV topography in migraine during childhood in order to elucidate the origin and cerebral generators of described CNV elevations. A large sample of children with primary headache (migraine with/without aura, tension type headache) and healthy controls aged 6-18 years was examined in a CNV paradigm using 64-channel high resolution DC-EEG. Patients were tested for diagnose-related topographic group differences of initial CNV (iCNV), late CNV (lCNV) and postimperative negative variation (PINV). All three CNV components of 6-11-year-old migraineurs without aura showed elevated negativity over the supplementary motor area (SMA) and around the vertex. Migraine children lacked age-dependent development of late CNV around Cz as previously reported. However, they showed a normal development of late CNV over pre-/primary motor cortex (MI). There was no marked elevation of iCNV amplitude over frontal areas (orienting reaction) nor specific amplitude elevations over "motor" or "sensory" areas during sustained attention (late CNV). Additional "pre-mature" activation e.g., in the locus coeruleus (leading to diffuse cortical activation summing up to a maximum over the vertex) or the basal ganglia (interacting with SMA) explained the rather stereotyped CNV elevation around the vertex better than a specific implication of the cortical systems responsible for orienting, motor preparation or sensory attention.     

Electrophysiological studies on headache: the contingent negative variation

The contingent negative variation (CNV) is a slow cortical potential recorded from the scalp. This method allows the pathophysiology of chronic headaches to be elucidated. When assessed during the pain-free interval patients suffering from migraine without aura show significantly more negative amplitudes than healthy controls. This negativity reflects the activity of cerebral noradrenergic systems. Some studies using repeated recordings of the CNV show a periodicity in amplitude change. When migraine patients are assessed a few days before a migraine attack occurs, they show pronounced negativity, which normalized during the attack. Despite these interesting findings that are based on group comparisons, evaluating the CNV on an individual basis does not allow specific conclusions. Thus, assessment of the CNV is an important tool to examine pathophysiological aspects of chronic headaches, but is not suitable as a diagnostic procedure.     

Is increased amplitude of contingent negative variation in migraine due to cortical hyperactivity or to reduced habituation?

The aim of this study was to compare the habituation kinetics of contingent negative variation (CNV) between 12 migraineurs without aura and matched healthy controls. CNV was studied with a 3 sec interval between the warning stimulus (WS) and the imperative stimulus (IS). The data from (a) the total interval (WS-IS), (b) early component, and (c) late component were analyzed. During successive trials the habituation kinetics were determined using regression analysis. On CNV averaged over 32 trials, migraine patients had a significantly higher negativity in the total interval compared to controls. When sequential blocks of four trials were analyzed, the most significant finding in migraineurs was lack of habituation of the early CNV component. The present study indicates that a delayed habituation, rather than a general increased cortical activity, is responsible for the CNV abnormalities in migraine without aura. We suggest that migraineurs between attacks not only have a cortical hyperexcitability, but also a lack of cortical inhibition causing delayed habituation.     

Slow cortical potentials in migraine families

Amplitude and habituation of event-related potentials are abnormal in migraine. We investigated 43 migraine and 41 healthy families to evaluate the influences of age, sex and familial contribution on the variance of amplitude and habituation of the contingent negative variation (CNV). Analysis of individual differences in relation to the CNV habituation was performed. The study demonstrated that habituation of the early CNV component characterizes migraine considerably better than the CNV amplitudes. Habituation, however, is strongly influenced by age. Migraine adults and children generally showed reduced habituation. Surprisingly, more than 30% of the healthy adults demonstrated a marked loss of habituation. The reduced CNV habituation represented a high sensitivity but low specificity to migraine, especially in children. CNV amplitude and habituation parameters revealed a considerable familial contribution associated with migraine. No familial influence on either morphology or habituation of the CNV in healthy families or between healthy members of migraine families was observed. The low specificity and familial transmission of CNV parameters in members of migraine families suggest that increased amplitudes and reduced habituation of CNV do not constitute a primary risk factor for migraine, but rather represent a predisposition. Genetic components probably affect variation of the CNV amplitude and habituation.     

Contingent negative variation in patients with chronic daily headache

The aim of this study was the investigation of amplitude and habituation of contingent negative variation (CNV) in migraine and chronic daily headache (CDH) patients in order to describe possible neurophysiological features responsible for the clinical transformation and worsening of the headache. Fifteen females suffering from migraine without aura and 15 females diagnosed with CDH evolved from migraine without aura with interparoxysmal chronic tension-type headache (transformed migraine), underwent CNV recording. Fifteen healthy females matched for age served as controls. CNV was obtained from C3 and C4 using the standard reaction time paradigm and 3 sec ISI. The amplitudes and habituation of total CNV, early and late components, and of post-imperative negative variation (PINV) were calculated. The migraine patients were characterized by significantly more pronounced negativity of the early component and total CNV, compared to CDH sufferers and controls. CDH patients demonstrated significantly reduced negativity of the late component and pronounced PINV compared to the other groups. The early component of CNV did not habituate in migraine or CDH patients. However, the impaired habituation in CDH was related to significantly lower amplitudes. These results support the diagnostic and scientific value of habituation in migraine research and therapy. Late components of CNV and PINV can be considered as predictive variables for transformation of migraine. The results are discussed in terms of the relationship between late CNV, PINV, environment control abilities and susceptibility for development of depression.     

A comparative study of oral acetylsalicyclic acid and metoprolol for the prophylactic treatment of migraine. A randomized, controlled, double-blind, parallel group phase III study

This study was a multinational, multicentre, double-blind, active controlled phase III trial designed to investigate efficacy and safety of 300 mg acetylsalicyclic acid (ASA) (n = 135) vs. 200 mg metoprolol (n = 135) in the prophylaxis of migraine. In total 270 (51 male and 219 female) patients, aged 18-65 years, suffering between two and six migraine attacks per month were recruited. The main objective was to show equivalence with respect to efficacy, defined as a 50% reduction in the rate of migraine attacks. A run-in phase was carried out with placebo for 4 weeks, followed by a 16-week drug phase. In both treatment groups the median frequency of migraine attacks improved during the study period, from three to two in the ASA group and from three to one in the metoprolol group; 45.2% of all metoprolol patients were responders compared with 29.6% with ASA. Medication-related adverse events were less frequent in the ASA group (37) than in the metoprolol group (73). The findings from this trial show that metoprolol is superior to ASA for migraine prophylaxis but has more side-effects. Acetylsalicylic acid is better tolerated than metoprolol. Using a strict responder criterion ASA showed a responder rate comparable with the placebo rate in the literature.     

Metoprolol in the Prophylaxis of Migraine: Parallel-Groups Comparison withPlacebo and Dose-Ranging Follow-Up

SYNOPSIS
88 patients in need of prophylactic treatment for classical, common or mixed migraine of at least 2years' duration were admitted to a double-blind placebo-controlled trial of the beta1-selective adrenoceptorblocker, metoprolol. All patients initially took placebo for 1 month, during which 29 were excludedprincipally because of failure to reattend or placebo-response making active treatment unnecessary. Theremaining 59 patients were randomised to continued placebo or metoprolol 50 mg b.i.d. for 2 months.Patients after this time subjectively categorizing their responses as less than optimal changed,double-blindly, from placebo to metoprolol 50 mg b.i.d., or from metoprolol 50 mg b.i.d. to 100 mg b.i.d., fora further follow-up period of up to 3 months.
Placebo response was 40% overall, and often occurred after the first month. In the first double-blindcomparative period metoprolol reduced attack frequency significantly, and more than placebo. Severity ofattacks still occurring was not altered by either treatment. Other measures of illness were alteredconsistently with these principal findings. Consistent improvements also were seen in patients switchingfrom initial placebo therapy to metoprolol 50 mg b.i.d. for the further follow-up period, and those changingto the higher dose of metoprolol showed statistically significant further improvements, and clinicallyimportant improvements overall. Side-effects were minor and reversible.
This study gives supportive evidence of the value of metoprolol in preventing migraine attacks andsuggests that individual dosage titration can substantially enhance its efficacy. Side-effects do notsignificantly impede its use and other evidence suggests that beta1-selective blockers are to be preferredover non-selective in migraine therapy.     

Perimenstrual Migraine: Effect of Estraderm TTS(r) and the Value of Contingent Negative Variation and Exteroceptive Temporalis Muscle Suppression Test

SYNOPSIS
In 20 patients with pure menstrual migraine either Estraderm TTS 50° patches (E) or placebo (P) patches were applied during three successive menstrual cycles, randomly allocated to the treatment sequences E-P-E or P-E-P. Clinical neurophysiological tests, contingent negative variation (CNV) and exteroceptive temporalis muscle suppression test (ETST) were performed before treatment. The predictive value of these tests regarding the efficacy of Estraderm TTS was studied.
Neither the number, duration and severity of the migraine attacks, nor the consumption of analgesics and ergotamine differed significantly during Estraderm TTS and placebo treatment.
The ETST was consistent with migraine in 35% (95% confidence interval 15.4 to 59.2) of the patients. The CNV in 55% (31.5 to 76.9), and both tests in 25% (8.7 to 49.1%).
Regarding the prediction of the Estraderm TTS effect on the migraine attacks, the specificity of the ETST, CNV and the combination of ETST with CNV, calculated for the first two cycles, was respectively 81.8% (48.2 to 97.7), 45.5% (16.8 to 76.6) and 80% (28.4 to 99.5). For the last two cycles these values were respectively 75% (42.8 to 94.5), 50.0% (21.1 to 87.9) and 71.4% (29.0 to 96.3). The sensitivity of the tests was respectively 62.5% (24.5 to 91.5), 62.5% (24.5 to 91.5) and 66.7% (22.3 to 95.7) in the first 2 cycles. In the last 2 cycles 50.0% (15.1 to 84.3), 62.5% (24.5 to 91.5) and 60% (14.7 to 94.7).
This study did not demonstrate an effectiveness of Estraderm TTS in perimenstrual migraine, except for the subgroup of perimenstrual migraine patients in whom the ETST test results were consistent with migraine.     

Contingent negative variation: methods and potential interest in headache

Contingent negative variation (CNV) is an event-related slow cerebral potential which has been found abnormal in migraine. Its methodology is described. Contrary to other neurophysiological techniques, CNV needs special equipment and expertise. On average, CNV amplitude is increased and its habituation is lacking in migraine without aura between attacks, but not in migraine with aura. The sensitivity of CNV as a diagnostic tool is low, but its specificity is high. CNV amplitude normalizes after treatment with beta-blockers. The CNV abnormalities in migraine might be due to hyperreactivity of central catecholaminergic pathways.     

Medikamentöse Migräneprophylaxe

If migraine attacks occur more frequently than 2 times a month, treatment of the acute attack with analgesics and ergotamine becomes problematic. An acute relief of migraine symptoms will be achieved only at the risk of developing a drug-induced chronic headache. Therefore, if migraine attacks occur frequently prophylactic treatment should be considered. A bewildering variety of drugs have been discussed for migraine prophylaxis in the past few decades. Only a few of them can be accepted to be effective on the basis of reliable clinical studies. Others have failed to show any superiority to placebo treatment when tested in controlled drug trials for a period long enough to rule out the placebo response, which may simulate effectiveness at the beginning of the trial. The efficacy of metoprolol and propranolol has been demonstrated beyond any doubt. It seems, however, that other beta-blocking drugs are less effective or even ineffective. In more than 20% of patients even prolonged treatment with metoprolol or propranolol does not provide sufficient relief. Flunarizine may be tried in these patients, as long as side effects do not occur or can be tolerated by the patient. Whether non-steroidal antirheumatics and dihydroergotamine can be considered as an effective and safe alternative in migraine prophylaxis is still not well established. There is, however, convincing evidence that neither clonidine, nor anti-histamines, nor barbiturates, nor antiepileptic drugs, nor anxiolytics are effective in the prophylactic treatment of migraine. Successful prophylactic treatment cannot be achieved by drug therapy alone. Any form of drug treatment should be complemented by providing the patient with detailed information about the nature of the disease and the properties of the prescribed drugs, as well as careful investigation of the patient's situation and habits and a careful search for precipitants, combined with an attempt to change the patient's habits and to avoid factors that trigger the attacks.     

Lack of age-dependent development of the contingent negative variation (CNV) in migraine children?

Increased negativity of contingent negative variation (CNV) in adult migraineurs is thought to reflect cortical hyperexcitability. CNV amplitude changes with age in healthy adults. Recently, evidence emerged that this might not be the case for migraineurs. Our study investigates age-dependency of CNV during childhood age. Seventy-six healthy controls and 61 children with migraine without aura (IHS code 1.1) between 6 and 18 years were examined using an acoustic S1-S2-CNV-paradigm with a 3-s inter-stimulus interval. The amplitude of the late component of CNV, as well as total CNV at the vertex (Cz according to the international 10-20 system), were significantly higher in migraineurs without aura than in controls. Healthy controls showed increasing amplitudes of CNV with age, whereas in migraine children without aura amplitudes did not change. Thus group differences were reduced during adolescence. Increased CNV negativity might reflect a biological vulnerability to migraine, rather than being a result of chronification. Migraineurs seem to lack age-dependent development of CNV also during early age, which supports the hypothesis of migraine as a maturation disorder.     

Botulinum toxin A in the prophylactic treatment of migraine--a randomized, double-blind, placebo-controlled study

Botulinum toxin A has been suggested to be effective in the prophylactic treatment of migraine. However, only very few randomized, double-blind, placebo-controlled studies are available. We designed such a study with a specific focus on different injection sites. Sixty patients with a migraine according to the criteria of the International Headache Society were randomly assigned to receive either placebo in the frontal and neck muscles, or to receive 16 U botulinum toxin A in the frontal muscles and placebo in the neck muscles, or to receive in total 100 U botulinum toxin A in the frontal and neck muscles. The observation period was 3 months. In both treatment groups, 30% of patients showed a reduction of migraine frequency in month 3 by at least 50% compared with baseline, in the placebo group 25% of the patients showed such a reduction (P = 0.921). There were no significant differences between the three study groups with respect to reduction of migraine frequency, number of days with migraine, and the number of total single doses to treat a migraine attack. In the post hoc analysis, the reduction of all accompanying symptoms was significantly higher in the 16 U treatment group compared with the placebo group. In the 100 U treatment group significantly more adverse events occurred compared with the placebo group. All adverse events were mild and transient. Our study did not show any efficacy of botulinum toxin A in the prophylactic treatment of migraine. Only accompanying symptoms were significantly reduced in the 16 U but not in the 100 U treatment group. Future studies should focus on the efficacy of botulinum toxin A in specific subgroups of patients, on the efficacy of repetitive injections, and on other injection sites.     

Contingent negative variation-findings and perspectives in migraine

Contingent negative variation (CNV) is a negative cerebral potential which is related to attention and arousal. CNV occurs during an experimental situation in which stimuli and responses are serially organized. Between attacks migraine patients have on average higher negative amplitudes compared to healthy controls or patients with tension-type headache. Successful treatment with beta-blocking agents decreases CNV amplitudes. In spite of encouraging findings in neurological disorders, CNV is not widely used. In this review some possible reasons for this are pointed out.